(Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4&#39;-trifluoromethylphenyl)-amide tablet formulations with improved stability

ABSTRACT

The invention relates to solid pharmaceutical compositions comprising (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4′-trifluoromethylphenyl)-amide, as well as a process for the preparation of the same, methods of using such compositions to treat subjects suffering from autoimmune diseases in particular systemic lupus erythematosus or chronic graft-versus-host disease, multiple sclerosis or rheumatoid arthritis.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical compositions comprising(Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4′-trifluoromethylphenyl)-amide,commonly known as Teriflunomide, as well as a process for thepreparation of the same, methods of using such compositions to treatsubjects suffering from autoimmune diseases in particular systemic lupuserythematosus or chronic graft-versus-host disease or multiple sclerosisor rheumatoid arthritis.

BACKGROUND OF THE INVENTION

(Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4′-trifluoromethylphenyl)-amide(Teriflunomide) has the structure illustrated in Formula I:

(Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4′-trifluoromethylphenyl)-amide(Teriflunomide, Formula I) use in treating chronic graft-versus-hostdisease has been disclosed in U.S. Pat. No. 4,965,276 issued on Oct. 23,1990. U.S. Pat. No. 5,459,163 issued on Oct. 21, 1997 and U.S. Pat. No.5,679,709 issued on Oct. 21, 1997 disclose compositions useful fortreating autoimmune diseases in particular lupus erythematosus.Teriflunomide has been shown to produce antiproliferative effects on awide variety of immune cells and cell lines (Cherwinski H. M., et al., JPharmacol. Exp. Ther. 1995; 272:460-8; Prkash A., et al., Drugs 1999;58(6):1137-66; Bartlett R. R. et al., Agent Action 1991; 32(1-2):10-21).Additionally, it inhibits the enzyme dihydroorotate dehydrogenase, anenzyme essential for the synthesis of pyrimidines (Bruneau J-M, et al.,Biochem. J. 1998; 36:299-303). European Patent 1381356 B1 discloses theuse of Teriflunomide for the manufacture of a medicament for treatingmultiple sclerosis wherein said medicament is administered orally.International Application WO 2007/118684 discloses Leflunomidecontaining solid pharmaceutical compositions including an organic orinorganic acid characterized by improved stability. Said compositionsshow a slighter decomposition of Leflunomide to Teriflunomide than incommercial Arava® tablets. Teriflunomide amounts are disclosed whichrange from 0.02 mg to 0.511 mg per tablet containing 10 mg ofLeflunomide. These are less than 0.35% Teriflunomide with respect to thetotal mass of the tablet, which is 150 mg.

A solid pharmaceutical formulation for Teriflunomide was developed foruse in clinical studies. One of the observations made during stabilitystudies was a strong increase in one degradant, which is2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide and has the structureillustrated in Formula II:

At room temperature storage2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide levels of up to 0.2% arereached in the solid pharmaceutical formulation after 12 month storage[Teriflunomide 7 mg tablets, Al/PVC blisters, storage at 25±2° C. and60% relative humidity {RH}]. A further degradant could be4-trifluoromethyl-aniline.

It is an object of the present invention to find a solid pharmaceuticalformulation for Teriflunomide which does not have the disadvantages ofincreased concentrations of2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide or4-trifluoromethyl-aniline (4-TFMA).

It has been found that some solid pharmaceutical formulations forTeriflunomide without colloidal silicon dioxide do not have thedisadvantages mentioned which is limited increase in2-cyano-N-(4-trifluoromethyl-phenyl)acetamide formation and limitedformation of 4-TFMA

It has further been found advantageous to add an acidic reactingcompound to said solid pharmaceutical formulation for Teriflunomidewithout colloidal silicon dioxide.

It has also been additionally found advantageous to add an acid reactingcompound to solid formulations of Teriflunomide containing colloidalsilicon dioxide.

SUMMARY OF THE PRESENT INVENTION

The present invention is a solid pharmaceutical composition comprisingabout 1% to 30% weight:weight (w:w) Teriflunomide, or a pharmaceuticallyacceptable basic addition salt thereof, about 5% to 20% weight:weightdisintegrant, about 0% to 40% weight:weight binder, about 0.1% to 2%weight:weight lubricant and the remaining percentage comprising diluentsprovided that said solid pharmaceutical composition does not containcolloidal silicon dioxide.

A second aspect of the invention is a solid pharmaceutical compositioncomprising about 1% to 20% weight:weight Teriflunomide, or apharmaceutically acceptable basic addition salt thereof, about 5% to 20%weight:weight disintegrant, about 0% to 30% weight:weight binder, about0.1% to 2% weight:weight lubricant, about 1% to 20% weight:weight acidicreacting compound and the remaining percentage comprising diluents.

A third aspect of the invention is a solid pharmaceutical compositioncomprising about 1% to 20% weight:weight Teriflunomide, or apharmaceutically acceptable basic addition salt thereof, about 5% to 20%weight:weight disintegrant, about 0% to 30% weight:weight binder, about0.1% to 2% weight:weight lubricant, about 1% to 20% weight:weight acidicreacting compound, about 0.1% to 0.5% weight:weight colloidal silicondioxide and the remaining percentage comprising diluents.

DETAILED DESCRIPTION OF THE INVENTION

The preparation according to the invention therefore provides a solidpharmaceutical composition comprising

-   -   a) about 1% to 30% weight:weight Teriflunomide, or a        pharmaceutically acceptable basic addition salt thereof,    -   b) about 5% to 20% weight:weight disintegrant,    -   c) about 0% to 40% weight:weight binder,    -   d) about 0.1% to 2% weight:weight lubricant and    -   e) the remaining percentage comprising diluents,        provided that said solid pharmaceutical composition does not        contain colloidal silicon dioxide.

Terms used herein have the meanings defined in this specification.

“Colloidal silicon dioxide” is submicroscopic fumed silica, also knownas pyrogenic silica. It is a non-crystalline, fine grain, low densityand high surface area silica. Primary particle size is from 5 nm to 50nm. The particles are non-porous and have a surface from 50 m²/g to 600m²/g. It can be obtained for example under the trade name Aeorsil 200Pharma from Evonik Industries [Evonik Degussa GmbH, Inorganic Materials,Weissfrauenstraße 9, 60287 Frankfurt, Germany] or under the trade nameCAB-O-SIL M-5P/5DP Cabot Corporation headquartered at Boston, Mass.,U.S.A.

“Degradant” refers to any drug-based materials generated after thepreparation of the unit dosage form. Analysis of impurities anddegradant is done using reverse phase HPLC techniques on extractedsamples as is known in the art.

“Pharmaceutically acceptable basic addition salt” is any non-toxicorganic or inorganic basic addition salt of the compound Teriflunomide.Illustrative inorganic bases which form suitable salts include potassiumhydroxide, sodium hydroxide, L-lysine or calcium hydroxide.

“Patient” means a warm blooded animal, such as for example rat, mice,dogs, cats, guinea pigs, and primates such as humans.

“Treat” or “treating” means any treatment, including, but not limitedto, alleviating symptoms, eliminating the causation of the symptomseither on a temporary or permanent basis, or preventing or slowing theappearance of symptoms and progression of the named disorder orcondition.

“Therapeutically effective amount” means an amount of the compound,which is effective in treating the named disorder or condition.

“Stereoisomers” is a general term for all isomers of the individualmolecules that differ only in the orientation of their atoms in space.It includes mirror image isomers (enantiomers), geometric (cis/trans)isomers, and isomers of compounds with more than one chiral center thatare not mirror images of one another (diastereoisomers).

“Teriflunomide” is the generic name for the compound(Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4′-trifluoromethylphenyl)-amide.Teriflunomide can be used in the form in which it is chemicallyprepared, or it can be subjected to a process which changes the physicalnature of the particles. For example, the material can be milled by anyprocess known in the art. Non exclusive examples of such processesinclude mechanical milling and jet milling. The particles producedeither directly from the process of chemically preparing Teriflunomideor after a milling operation preferably provide average particlediameters in the range of 1 μm to 100 μm. It is advantageous to use saidTeriflunomide particles from 1 μm to 100 μm in the preparation of thesolid pharmaceutical composition, especially at about 1% to 10%weight:weight of Teriflunomide.

The synthesis of Teriflunomide has been disclosed, and is accomplishedby methods that are well known to those skilled in the art. For example,U.S. Pat. No. 5,990,141, issued on Nov. 23, 1999 discloses methods ofsynthesis.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising a therapeutically effective amount ofteriflunomide or a pharmaceutically acceptable basic addition saltthereof, wherein the solid pharmaceutical composition does not containcolloidal silicon dioxide.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising from about 2% to 15% weight:weight Teriflunomideand the other components disintegrant, binder, lubricant and diluentsshow the same amount as defined under b) to e) above.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising from about 7% to 15% weight:weight disintegrantand the other components Teriflunomide, binder, lubricant and diluentsshow the same amount as defined under a) and c) to e) above.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising from about 15% to 35% weight:weight binder andthe other components Teriflunomide, disintegrant, lubricant and diluentsshow the same amount as defined under a), b), d) and e) above.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising from about 0.1% to 1.0% weight:weight lubricantand the other components Teriflunomide, disintegrant, binder anddiluents show the same amount as defined under a) to c) and e) above.

Examples of disintegrants are carboxymethylcellulose, low substitutedhydroxyproyl cellulose, microcrystalline cellulose, powdered cellulose,croscarmellose sodium, methylcellulose, polacrilin potassium, sodiumalginate, sodium starch glycolate or a mixture of one or more of saiddisintegrants.

Examples of binders are acacia, carboxymethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose, dextrin, gelatin, guargum, hydroxypropyl methylcellulose, maltodextrin, methylcellulose,sodium alginate, pregelatinized starch, starches such as potato starch,corn starch or cereal starch and zein or a mixture of one or more ofsaid binders.

Examples of lubricants are calcium stearate, glyceryl palmitostearate,sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearicacid, talc, zinc stearate and magnesium stearate or a mixture of one ormore of said lubricants.

Examples of diluents are cellulose, cellulose acetate, dextrates,dextrin, dextrose, fructose, 1-O-α-D-Glucopyranosyl-D-mannitol, glycerylpalmitostearate, hydrogenated vegetable oil, kaolin, lactitol, lactose,lactose mono-hydrate, maltitol, mannitol, maltodextrin, maltose,pregelatinized starch, sodium chloride, sorbitol, starches, sucrose,talc and xylitol or a mixture of one or more of said diluents.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising from 2% to 15% weight:weight Teriflunomide, 7% to15% weight:weight disintegrant selected from one or more ofmicrocrystalline cellulose or sodium starch glycolate, 15% to 35%weight:weight binder selected from one or more of hydroxyproylcelluloseor corn starch, 0.1% to 1.0% weight:weight lubricant selected frommagnesium stearate and the remaining percentage comprising diluentsselected from lactose mono-hydrate.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising

-   -   A) about 1% to 20% weight:weight Teriflunomide, or a        pharmaceutically acceptable basic addition salt thereof,    -   B) about 5% to 20% weight:weight disintegrant,    -   C) about 0% to 30% weight:weight binder,    -   D) about 0.1% to 2% weight:weight lubricant,    -   E) about 1% to 20% weight:weight acidic reacting compound and    -   F) the remaining percentage comprising diluents.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising from about 2% to 15% weight:weight Teriflunomideand the other components disintegrant, binder, lubricant, acidicreacting compound and diluents show the same amount as defined under B)to F) above.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising from about 7% to 15% weight:weight disintegrantand the other components Teriflunomide, binder, lubricant, acidicreacting compound and diluents show the same amount as defined under A)and C) to F) above.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising from about 15% to 30% weight:weight binder andthe other components Teriflunomide, disintegrant, lubricant, acidicreacting compound and diluents show the same amount as defined under A),B) and D) to F) above.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising from about 0.1% to 1.0% weight:weight lubricantand the other components Teriflunomide, disintegrant, binder, acidicreacting compound and diluents show the same amount as defined under A)to C), E and F) above.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising from about 3% to 20% weight:weight acidicreacting compound and the other components Teriflunomide, disintegrant,binder, lubricant and diluents show the same amount as defined under A)to D) and F) above.

Examples of acidic reacting compound are citric acid, acetic acid,glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid,glutaric acid, fumaric acid, malic acid, tartaric acid, ascorbic acid,maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid,phenylacetic acid, cinnamic acid, salicyclic acid, 2-phenoxybenzoicacid, p-toluenesulfonic acid and sulfonic acids such as methanesulfonicacid and 2-hydroxyethanesulfonic acid or a mixture of one or more ofsaid acidic reacting compound.

Teriflunomide is mixed with said disintegrant, binder, lubricant anddiluents constituents to obtain the concentration of Teriflunomide andsaid further components according to the present invention in the finalmixture and finally is mixed with an acidic reacting compound. In afurther embodiment of the invention the solid pharmaceutical compositioncomprising components A) to F) as defined above shows a pH from 4.5 to2.0, when water is adsorbed to the pharmaceutical composition or whenwater is added in small amounts to the pharmaceutical composition. In afurther embodiment of the invention the solid pharmaceutical compositioncomprising components A) to F) as defined above shows a pH from about pH3 to about pH 2.

The pH determination is performed by suspending one tablet in about 1 mlof purified water. The pH of the supernatant is determined with a pHsensitive probe.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising a therapeutically effective amount ofteriflunomide or a pharmaceutically acceptable basic addition saltthereof, wherein the pH of the solid pharmaceutical composition is lessthan about 4.5, particularly from about 4.5 to about 2.0, moreparticularly from about 3 to about 2.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising

-   -   A) about 1% to 20% weight:weight Teriflunomide, or a        pharmaceutically acceptable basic addition salt thereof,    -   B) about 5% to 20% weight:weight disintegrant,    -   C) about 0% to 30% weight:weight binder,    -   D) about 0.1% to 2% weight:weight lubricant,    -   E) about 1% to 20% weight:weight acidic reacting compound,    -   F) about 0.1% to 0.5% weight:weight colloidal silicon dioxide        and    -   G) the remaining percentage comprising diluents.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising from about 2% to 15% weight:weight Teriflunomideand the other components disintegrant, binder, lubricant, acidicreacting compound, colloidal silicon dioxide and diluents show the sameamount as defined under B) to G) above.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising from about 7% to 15% weight:weight disintegrantand the other components Teriflunomide, binder, lubricant, acidicreacting compound, colloidal silicon dioxide and diluents show the sameamount as defined under A) and C) to G) above.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising from about 15% to 30% weight:weight binder andthe other components Teriflunomide, disintegrant, lubricant, acidicreacting compound, colloidal silicon dioxide and diluents show the sameamount as defined under A), B) and D) to G) above.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising from about 0.1% to 1.0% weight:weight lubricantand the other components Teriflunomide, disintegrant, binder, acidicreacting compound, colloidal silicon dioxide and diluents show the sameamount as defined under A) to C), E and G) above.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising from about 3% to 20% weight:weight acidicreacting compound and the other components Teriflunomide, disintegrant,binder, lubricant, colloidal silicon dioxide and diluents show the sameamount as defined under A) to D) and F) and G) above.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising from about 0.2% to 0.4% weight:weight colloidalsilicon dioxide and the other components Teriflunomide, disintegrant,binder, lubricant, acidic reacting compound and diluents show the sameamount as defined under A) to E) and G) above.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising from about 0.3% weight:weight colloidal silicondioxide and the other components Teriflunomide, disintegrant, binder,lubricant, acidic reacting compound and diluents show the same amount asdefined under A) to E) and G) above.

Teriflunomide is mixed with said disintegrant, binder, lubricant,colloidal silicon dioxide and diluents constituents to obtain theconcentration of Teriflunomide and said further components according tothe present invention in the final mixture and finally is mixed with anacidic reacting compound. In a further embodiment of the invention thesolid pharmaceutical composition comprising components A) to G) asdefined above shows a pH from 4.5 to 2.0, when water is adsorbed to thepharmaceutical composition or when water is added in small amounts tothe pharmaceutical composition. In a further embodiment of the inventionthe solid pharmaceutical composition comprising components A) to G) asdefined above shows a pH from about pH 3 to about pH 2.

In providing Teriflunomide formulations in forms suitable for unitdosage formation, the Teriflunomide and the further components of thesolid pharmaceutical composition according to the invention can be mixedas powders. This mixing can be carried out using any of the mixingtechniques known in the art. The mixing is preferably carried out usinga high shear mixer, V-blender (or other twin-shell blender), bin blenderor Turbula mixer-shaker. Blending is typically carried out first withoutthe addition of a lubricant for sufficient time to assure completemixing. At that point, the lubricant is typically added followed by ashort (about 1-10 minute) further mixing period. Once the blend is made,unit dosage forms are prepared by procedures known in the art.Preferably, unit dosage forms are made on rotary tablet presses orcapsule filling machines. The dosage forms thus prepared can thenoptionally be coated with a film designed to provide ease of swallowing,a proprietary or identification appearance and/or protection of thedosage form.

Alternatively, preferred processes for preparing a wet granulation ofTeriflunomide and the further components of the solid pharmaceuticalcomposition comprise the following steps:

-   -   (a) blending of the Teriflunomide with diluent and optionally        some or all of the remaining excipients needed for the final        composition. These other excipients can include binders,        disintegrant, lubricant, acidic reacting compound and colloidal        silica;    -   (b) adding a granulation solvent while the material from        step (a) is under shear. Preferred granulation solvents include,        water, ethanol, isopropanol and combinations thereof. Other        ingredients can be added to the granulation solvent as known in        the art. Examples of such additives are binders, acidic reacting        compounds, wetting agents, stabilizers and buffers. The solvent        can be applied by any technique known in the art. Preferred        methods of applying the solvent while imparting shear include        high shear granulation, low shear granulation, fluid bed        granulation and extrusion granulation;    -   (c) optionally, the material from step (b) can be milled, ground        or sieved. This wet material is then dried, preferably using air        drying, fluid bed drying, oven drying or microwave drying. The        drying is preferably carried out such that the drying        temperature does not exceed about 60° C.;    -   (d) optionally this material is then milled or sieved;    -   (e) the material is then blended with additional excipients; and    -   (f) the composition is optionally formed into a unit dosage        form, preferably a tablet or a capsule.

The dosage forms thus prepared can then optionally be coated with a filmdesigned to provide ease of swallowing, a proprietary or identificationappearance and/or protection of the dosage form.

The final dosage form is then packaged using procedures known in theart. For the present invention, the packaging is preferably in the formof foil-foil cold form blisters, plastic blisters or sealed bottles withor without desiccant. For blisters packaging materials with a watervapor permeability below 0.25 g/m²/day are preferred.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising a therapeutically effective amount ofteriflunomide or a pharmaceutically acceptable basic addition saltthereof, wherein the solid pharmaceutical composition contains no morethan about 0.1%, or particularly no more than about 0.05% by weight of2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide after being stored atabout 25° C. and about 65% relative humidity for about 12 months.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising a therapeutically effective amount ofteriflunomide or a pharmaceutically acceptable basic addition saltthereof, wherein the solid pharmaceutical composition contains no morethan about 0.3%, or particularly no more than about 0.2%, or moreparticularly no more than about 0.05% by weight of2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide after being stored atabout 25° C. and about 65% relative humidity for about 36 months.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising a therapeutically effective amount ofteriflunomide or a pharmaceutically acceptable basic addition saltthereof, wherein the solid pharmaceutical composition contains no morethan about 0.3%, particularly no more than about 0.1%, or moreparticularly no more than about 0.05% by weight of2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide after being stored atabout 30° C. and about 65% relative humidity for about 12 months.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising a therapeutically effective amount ofteriflunomide or a pharmaceutically acceptable basic addition saltthereof, wherein the solid pharmaceutical composition contains no morethan about 1%, or particularly no more than about 0.5%, or moreparticularly no more than about 0.05% by weight of2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide after being stored atabout 30° C. and about 65% relative humidity for about 36 months.

In a further embodiment the invention relates to a solid pharmaceuticalcomposition comprising a therapeutically effective amount ofteriflunomide or a pharmaceutically acceptable basic addition saltthereof, wherein the solid pharmaceutical composition contains no morethan about 0.3%, particularly no more than about 0.1%, or moreparticularly no more than about 0.05% by weight of2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide after being stored atabout 30° C. and about 75% relative humidity for about 12 months.

The solid pharmaceutical composition according to the invention can beadministered in any form or mode which makes the compound bioavailablein therapeutically effective amounts, including orally, sublingually,buccally, transdermally, intranasally, rectally, topically, and thelike. One skilled in the art of preparing formulations can determine theproper form and mode of administration depending upon the particularcharacteristic disease to be treated, the stage of the disease, thecondition of the patient and other relevant circumstances. For example,see Remington's Pharmaceutical Sciences, 18th Edition, Mack PublishingCo. (1990).

The solid pharmaceutical composition according to the invention may beadministered orally, for example, in the form of tablets, troches,capsules, wafers, chewing gums and the like.

Other dosage unit forms may contain other various materials, whichmodify the physical form of the dosage unit, for example, as coatings.Thus, tablets or pills may be coated with nonfunctional coatings likeHypromelose based coatings, sugar, shellac, or other enteric coatingagents.

The dosage range at which Teriflunomide exhibits its ability to acttherapeutically can vary depending upon its severity, the patient, otherunderlying disease states that the patient is suffering from, and othermedications that may be concurrently administered to the patient.Generally, Teriflunomide will exhibit their therapeutic activities atdosages of between about 0.001 mg/kg of patient body weight/day to about100 mg/kg of patient body weight/day.

The solid pharmaceutical composition according to the invention issuitable for example, for treating acute immunological events, such assepsis, allergy, graft-versus-host-reactions andhost-versus-graft-reactions, Autoimmune disease such as rheumatoidarthritis, systemic lupus erythematodes, or multiple sclerosis,psoriasis, asthma, urticaria, rhinitis and uveitis, cancerous diseasessuch as lung cancer, leukemia, ovarian cancer, sarcoma, Kaposi'ssarcoma, meningioma, intestinal cancer, lymph node cancer, braintumours, breast cancer, pancreatic cancer, prostate cancer or skincancer.

The following non-limiting examples illustrate the inventors' preferredmethods for preparing and using the pharmaceutical compositions of thepresent invention.

EXAMPLES Example 1 Manufacturing Process

Granulation Liquid:

Hydroxypropyl cellulose 7.5 mPa*s (HPC) and Citric acid monohydrate aredissolved in 219.3 g of purified water and are stirred for at least 30min. The concentration of HPC in the final solution is 6.4% relative tothe mass of water irrespective of the amount of citric acid added.(table 1).

TABLE 1 Compositions of granulation liquid Mass Citric MassHydorxypropyl Mass Total Mass Acid Cellulose water mass Citricacid/tablet [g] [g] [g] [g] 0 mg Citric Acid 0 14 219.3 233.3 2.5 mgCitric acid 10 14 219.3 243.3 5 mg Citric acid 20 14 219.3 253.3 20 mgCitric acid 80 14 219.3 313.3 25 mg Citric acid 100 14 219.3 333.3

Tablets:

-   1. Teriflunomide, Lactose or Mannitol (0C and 0D), Corn starch and    if necessary citric acid monohydrate (1D and 1J) are blended for 5    min in a fluid bed granulator (UNI-Glatt, flap 25%, inlet air    temperature ˜23° C., shaking interval 30 sec, shaking 5 sec).-   2. The resulting blend is granulated with a solution of HPC and if    necessary citric acid in a fluid bed granulator (UNI Glatt, flap    25-30%, inlet air temperature 60° C., shaking interval 60 sec,    shaking 5 sec, spray rate ˜12.5 g/min, atomizing air pressure 1 bar,    nozzle diameter 0.8 mm). Duration approx. 25 min-   3. The granules are dried in a fluid bed granulator for approx. 20    min (UNI Glatt, flap 25-30%, inlet air temperature 60° C., shaking    interval 60 sec, shaking 5 sec).-   4. The granules are calibrated through a 1 mm sieve and are    lubricated with microcrystalline cellulose, sodium starch glycollate    and if necessary with colloidal silicon dioxide (Examples 1F-1J) in    a turbula blender [2 L glass container] for 5 min.-   5. After addition of Magnesium stearate the mixture is blended for    another minute in a turbula blender [2 L glass container].

The final blend is compressed to tablets on a Korsch EK0 single punchpress.

The composition of the solid pharmaceutical compositions prepared isgiven in tables 1,2 and 3.

TABLE 1 Composition of Teriflunomide tablets with and without colloidalsilicon dioxide (0A to 0E) Example 0A 0B 0C 0D 0E Teriflunomide [mg]7.000 7.000 7.000 7.000 14.000 Lactose mono- 81.000 81.000 xx xx 76.000hydrate [mg] Mannitol [mg] xx xx 101.0 101.0 xx Corn starch [mg] 40.00040.000 20.00 20.00 38.00 Hydroxypropyl 3.500 3.500 3.500 3.500 3.500cellulose [mg] Mass granules 131.500 131.500 131.500 131.500 131.500[mg] Microcrystalline 10.500 10.000 10.000 10.500 10.500 Cellulose [mg]Sodium starch 7.500 7.500 7.500 7.500 7.500 glycolate [mg] Colloidalsilicon xx 0.500 0.500 xx xx dioxide [mg] Magnesium 0.500 0.500 0.5000.500 0.500 stearate [mg] Total mass [mg] 150.000 150.000 150.000150.000 150.000 In the above table “xx” means no addition of thecomponent

TABLE 2 Composition of Teriflunomide tablets acidified with Citric acidand without colloidal silicon dioxide Example 1A 1B 1C 1D Teriflunomide[mg] 7.000 7.000 7.000 7.000 Lactose mono- 78.500 78.000 65.000 65.000hydrate [mg] Corn starch [mg] 40.000 38.000 31.000 31.000 Citric acid xxxx xx 5.000 (solid) [mg] Citric acid 2.500 5.000 25.000 20.000(dissolved) [mg] Hydroxypropyl 3.500 3.500 3.500 3.500 cellulose [mg]Mass granules 131.500 131.500 131.500 131.500 [mg] Microcrystalline10.500 10.500 10.500 10.500 Cellulose [mg] Sodium starch 7.500 7.5007.500 7.500 glycolate [mg] Colloidal silicon xx xx xx xx dioxide [mg]Magnesium 0.500 0.500 0.500 0.500 stearate [mg] Total mass [mg] 150.000150.000 150.000 150.000 pH of tablet 3.3 2.9 2.2 2.2 In the above table“xx” means no addition of the component

TABLE 3 Composition of Teriflunomide tablets acidified with citric acidand with colloidal silicon dioxide Example 1G 1H 1I 1J Teriflunomide[mg] 7.000 7.000 7.000 7.000 Lactose mono- 78.500 78.000 65.000 65.000hydrate [mg] Corn starch [mg] 40.000 38.000 31.000 31.000 Citric acid xxxx xx 5.000 (solid) [mg] Citric acid 2.500 5.000 25.000 20.000(dissolved) [mg] Hydroxypropyl 3.500 3.500 3.500 3.500 cellulose [mg]Mass granules 131.500 131.500 131.500 131.500 [mg] Microcrystalline10.000 10.000 10.000 10.000 Cellulose [mg] Sodium starch 7.500 7.5007.500 7.500 glycollate [mg] Colloidal silicon 0.500 0.500 0.500 0.500dioxide [mg] Magnesium 0.500 0.500 0.500 0.500 stearate [mg] Total mass[mg] 150.000 150.000 150.000 150.000 pH of tablet 3.5 2.9 2.1 2.1 In theabove table “xx” means no addition of the component

Example 2 Formation of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide

(A) Manufacturing of the Tablets

The tablets are prepared according to the manufacturing process given inexample 1.

The composition of the tablets is given in tables 1, 2 and 3.

Storage of the Tablets

The samples are stored for up to 6 months at 25° C./60% RH, 30° C./65%RH, 40° C./75% RH in induction sealed HDPE bottles [wide necked bottle,45 mL, white, round with induction seal and child resistant screw cap]and at 40° C./75% RH in open glass bottles. Bottles are stored upright.

Analysis of the Samples

Tablets are analyzed for content by HPLC.

The content of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide intablets, acidified with citric acid with our without colloidal silicondioxide, is given in table 4.

TABLE 4 Formation of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide intablets with and without colloidal silicon dioxide (0A and 0B) and inacidified tablets without colloidal silicon dioxide (1A to 1D) ExampleStorage 1A 1B 1C 1D 0A 0B (Reference) Month conditions2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide [%] 0 Initial Mean 0.01300.0105 0.0123 0.0111 0.0143 0.0302 RSD 10.1030 14.718 3.5217 17.04513.5157 3.8501 1 40° C./75% RH Mean 0.0383 0.0449 0.0699 0.0481 0.03530.0919 RSD 0.7039 1.6998 33.095 0.6950 2.7145 1.7791 1 40° C./75% RHopen Mean 0.1360 0.1490 0.0664 0.0683 0.0863 0.1283 RSD 0.9016 1.47201.7785 2.5879 2.3490 2.0459 3 25° C./60% RH Mean 0.0274 0.0196 0.02670.0194 0.0242 0.0431 RSD 14.7830 5.3867 4.8454 5.4754 2.4537 2.4995 330° C./65% RH Mean 0.0378 0.0323 0.0438 0.0347 0.0351 0.0656 RSD 8.88417.1005 3.4361 4.9873 7.4946 2.8880 3 40° C./75% RH Mean 0.1390 0.15350.1091 0.1029 0.0807 0.1821 RSD 1.7326 2.5300 1.6702 0.6768 5.45021.0879 3 40° C./75% RH, open Mean 0.3006 0.3306 0.1509 0.1534 0.21070.2461 RSD 0.5967 0.6505 1.2309 0.6459 1.9609 2.3632 6 25° C./60% RHMean 0.0645 0.0341 0.0500 0.0369 0.0411 0.0824 RSD 4.3042 11.6345 4.52633.1312 3.6245 2.8094 6 30° C./65% RH Mean 0.0414 0.0689 0.0645 0.06940.0562 0.1396 RSD 7.4586 4.2140 2.5329 4.2497 8.4947 1.2221 6 40° C./75%RH Mean 0.2920 0.3592 0.1846 0.1829 0.1542 0.4149 RSD 2.2691 1.72861.5597 1.9427 2.0578 1.3660 6 40° C./75% RH open Mean 0.6769 0.72000.2635 0.2799 0.4447 0.6194 RSD 0.3538 0.5624 0.8745 0.9602 1.21020.8003 “RSD” means relative standard deviation ((standard deviation ofarray X) × 100/(average of array X) = relative standard deviation). “RH”means relative humidity; the relative humidity of an air-water mixtureis defined as the ratio of the partial pressure of water vapor in themixture to the saturated vapor pressure of water at a prescribedtemperature.

In each batch 4 samples are determined at the beginning (0 month) after1, 3 and 6 months. Only mean and RSD of the tested samples are shown.

The content of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide in tabletsacidified with citric acid with colloidal silicon dioxide is given intable 5.

TABLE 5 Formation of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide inacidified tablets with colloidal silicon dioxide. Example 1G 1H 1I 1JStorage 2-cyano-N-(4-trifluoromethyl-phenyl)- Month conditions acetamide[%] 0 Initial Mean 0.0273 0.0215 0.0116 0.0120 RSD 1.5419 10.1026 7.77472.1246 1 40° C./75% RH Mean 0.0741 0.0704 0.0322 0.0416 RSD 1.37135.4415 5.6604 1.2491 1 40° C./75% RH open Mean 0.1561 0.1683 0.06160.0692 RSD 1.1244 1.3425 0.9626 4.3785 3 25° C./60% RH Mean 0.03560.0303 0.0140 0.0171 RSD 5.9774 9.5942 5.4163 7.1324 3 30° C./65% RHMean 0.0496 0.0461 0.0232 0.0261 RSD 5.4842 12.4861 6.2709 6.3572 3 40°C./75% RH Mean 0.1558 0.1664 0.0715 0.0867 RSD 2.8099 2.1597 1.63573.4267 3 40° C./75% RH, open Mean 0.3061 0.3181 0.1198 0.1346 RSD 0.99921.2165 3.0218 2.1899 6 25° C./60% RH Mean 0.0703 0.0650 0.0274 0.0362RSD 2.1623 1.1513 3.6860 6.7916 6 30° C./65% RH Mean 0.1099 0.11440.0511 0.0513 RSD 2.0462 2.1572 3.0849 5.2812 6 40° C./75% RH Mean0.3751 0.4286 0.1627 0.1768 RSD 1.0971 1.0910 1.1734 0.4281 6 40° C./75%RH open Mean 0.7496 0.7840 0.2765 0.2941 RSD 0.1725 0.6620 1.0646 0.4167

In each batch 4 samples are determined at the beginning (0 month), after1, 3 and 6 months. Only mean and RSD of the tested samples are shown.

After 3 or 6 months storage at the above-identified storage conditionsin HDPE bottles Teriflunomide tablets containing 25 mg citric acidlubricated with or without colloidal silicon dioxide [Examples 1 C, D,II, J] and Teriflunomide tablets containing no citric acid butlubricated without colloidal silicon dioxide (Example 0A) displaysignificantly reduced formation of2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide compared to Teriflunomidetablets containing colloidal silicon dioxide (Example 0B). In inductionsealed HDPE bottles, the stabilizing effect of citric acid is morepronounced in the presence of colloidal silicon dioxide.

The determination of Teriflunomide,2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide and 4-TFMA are performedby a gradient high performance liquid chromatographic system (HPLC) asfollows:

-   Stationary phase: Purospher STAR RP18e (3 μm)-   Column material: stainless steel-   Column length: 125 mm-   Column internal diameter: 4.0 mm-   Equilibration of the column: Column must be rinsed with the mobile    phase B for at least 15 min at a flow rate of 1.0 mL/min

Mobile Phase

Buffer is prepared by the transfer of 50 mmol (4.2 g) of sodium acetate,50 mmol (2.9 g) of sodium chloride in a glass bottle for mobile phasesand addition of 1000 mL water. Adjust pH to 6.5 with glacial acetic acidusing a pH-meter.

Mobile phase A Mobile phase B Buffer pH 6.5 900 mL Buffer pH 6.5 100 mLAcetonitrile 100 mL Acetonitrile 900 mL

Gradient:

Time Mobile phase A Mobile phase B [minutes] [%] [%] 0 100 0  0 to 20 5248 20 to 25 0 100 25 to 26 100 0 26 to 30 100 0

Procedure

-   Flow rate: 1.0 mL/minute-   Expected pressure drop: 220 bar-   Injection volume: 10 μL-   Auto sampler temperature: Set auto sampler temperature at +15° C.-   Column temperature: Set oven temperature at +20° C.-   Detection: 249 nm (UV)-   Typical reporting time: 25 minutes-   Typical total run time: 30 minutes-   Retention times:

Teriflunomide about 15.0 minutes 2-Cyano-N-(4-trifluoromethyl- about19.3 minutes phenyl)-acetamide 4-TFMA about 19.8 minutes

Example 3 pH Determination of the Tablets

The pH determination is performed by suspending one tablet in about 1 mlof purified water. After disintegration of the tablet and settling ofthe solid contents, the pH of the supernatant is determined with a pHsensitive probe. The mean result of two individual tablets is reportedas pH of tablet (see tables 2 and 3).

Example 4 Formation of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamideand 4-TFMA in Teriflunomide Tablets with and without Colloidal SiliconDioxide

Manufacturing of the Tablets

The tablets are prepared according to the manufacturing process given inexample 1.

The composition of the tablets is given in table 1.

Storage of the Tablets

In an additional stability study the samples are stored for 6 months at40° C./75% RH in induction sealed HDPE bottles [wide necked bottle, 60mL, white, round with induction seal and child resistant screw cap].Bottles are stored upright.

Analysis of the Samples

Tablets are analyzed for related impurities by HPLC (using the methoddescribed above).

The content of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide and of4-TFMA after 6 month storage at 40° C./75% RH in tablets with or withoutcolloidal silicon dioxide is given in table 6.

TABLE 6 Formation of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide andof 4- TFMA in tablets with and without colloidal silicon dioxide (0A and0B) Example Storage 0A 0B 0C 0D Month conditions2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide [%] 0 Initial Mean 0.0040.013 0.008 0.002 RSD 0.191 0.026 0.010 0.320 6 40° C./75% RH Mean 0.2130.543 0.600 0.241 RSD 0.006 0.001 0.001 0.001 Month 4-TFMA [ppm] 0Initial Mean 0.00 0.00 0.00 0.00 RSD — — — — 6 40° C./75% RH Mean 28 5748 22 RSD 0.049 0.035 0.244 0.050

After 6 months storage at the above-identified storage conditions inHDPE bottles Teriflunomide tablets lubricated without colloidal silicondioxide (Example 0A and 0D) display significantly reduced formation of2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide compared to Teriflunomidetablets containing colloidal silicon dioxide (Example 0B and 0C).Further more the formation of 4-TFMA is strongly reduced in tabletscontaining no colloidal silicon dioxide (Example 0A and 0D) compared totablets lubricated with colloidal silicon dioxide ((Example 0B and 0C).

The determination of Teriflunomide and2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide and 4-TFMA are performedby a gradient high performance liquid chromatographic system (HPLC) asdescribed in Example 2.

Example 5 Formation of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamideand 4-TFMA in Film-Coated Tablet

The samples of example 0A and 0E are made into hypromelose based, i.e.Opadry® or Spectrablend™ (5 mg/tablet) film-coated tablets and storedfor up to 36 months at 30° C./65% RH, 30° C./75% RH and 40° C./75% RHin:

-   -   ALU/PVC blisters (i.e. PVC (Polyvinyl chloride) 250 μm &        Aluminium sealing foil [20 μm, with PVC/acrylate heat sealable        coating]);    -   ALU/PVdC blisters (i.e. bilayer film of PVC (Polyvinyl chloride)        250 μm and 90 g/m² vinylidene chloride and acrylic acid        methylester Copolymer & Aluminium sealing foil [20 μm, with        PVC/acrylate heat sealable coating]);    -   ALU/PVC/PCTFE blisters (i.e. 254 μm PVC/75 μm PCTFE laminated        film & Aluminium sealing foil [20 μm, with PVC/acrylate heat        sealable coating]);    -   ALU/ALU blisters (i.e. PVC 60 μm/Aluminium foil 45 μm/Polyamide        25 μm & Aluminium foil [20 μm with PVC/acrylate heat sealable        coating]); or    -   HDPE bottles (i.e. high density polyethylene bottles with        polypropylene cap and aluminium induction seal and with or        without silica gel desiccant canister added).

TABLE 7 Formation of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide [%]of film-coated tablet up to 12 months storage Storage Example PackagingCondition 12 Months 0A ALU/PVC 30° C./65% RH 0.29% 0A ALU/PVdC 30°C./75% RH 0.21% 0A HDPE 60 mL 30° C./75% RH 0.09% 0A HDPE 45mL/desiccant 30° C./65% RH 0.06% 30° C./75% RH 0.09% 0A ALU/PVC/PCTFE30° C./65% RH 0.08% 0A ALU/ALU 30° C./65% RH 0.08% 0E ALU/PVC 30° C./65%RH 0.15% 0E ALU/PVdC 30° C./75% RH 0.12% 0E HDPE 60 mL 30° C./75% RH<0.05% 0E HDPE 45 mL/desiccant 30° C./65% RH <0.05% 30° C./75% RH <0.05%0E ALU/PVC/PCTFE 30° C./65% RH <0.05% 0E ALU/ALU 30° C./65% RH <0.05%

TABLE 8 Formation of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide [%]of film-coated tablet up to 36 months storage Storage Example PackagingCondition 36 Months 0A ALU/PVC 30° C./65% RH 0.94% 0A ALU/PVC/PCTFE 30°C./65% RH 0.41% 0A ALU/ALU 30° C./65% RH 0.20% 0E ALU/PVC 30° C./65% RH0.52% 0E ALU/PVC/PCTFE 30° C./65% RH 0.21% 0E ALU/ALU 30° C./65% RH<0.05

4-TFMA levels for tablets reported in Tables 7 and 8 are all below0.01%.

1. (canceled)
 2. A solid pharmaceutical composition comprising a) 1percent to 30 percent weight:weight teriflunomide, or a pharmaceuticallyacceptable basic addition salt thereof, b) 5 percent to 20 percentweight:weight disintegrant, c) 0 percent to 40 percent weight:weightbinder, d) 0.1 percent to 2 percent weight:weight lubricant, and e) theremaining percentage comprising diluents; wherein the solidpharmaceutical composition contains no more than about 0.5 percent byweight of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide.
 3. The solidpharmaceutical composition according to claim 2, wherein the solidpharmaceutical composition contains no more than about 0.0863% by weightof 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide after being stored inan open container at about 40° C. and about 75% relative humidity forabout one month.
 4. The solid pharmaceutical composition according toclaim 2, wherein the solid pharmaceutical composition contains no morethan about 0.0353% by weight of2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide after being stored in asealed container at about 40° C. and about 75% relative humidity forabout one month.
 5. The solid pharmaceutical composition according toclaim 2, wherein the solid pharmaceutical composition contains no morethan about 0.0242% by weight of2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide after being stored in asealed container at about 25° C. and about 60% relative humidity forabout three months.
 6. The solid pharmaceutical composition according toclaim 2, wherein the solid pharmaceutical composition contains no morethan about 0.0351% by weight of2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide after being stored in asealed container at about 30° C. and about 65% relative humidity forabout three months.
 7. The solid pharmaceutical composition according toclaim 2, wherein the solid pharmaceutical composition contains no morethan about 0.0807% by weight of2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide after being stored in asealed container at about 40° C. and about 75% relative humidity forabout three months.
 8. The solid pharmaceutical composition according toclaim 2, wherein the solid pharmaceutical composition contains no morethan about 0.2107% by weight of2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide after being stored in anopen container at about 40° C. and about 75% relative humidity for aboutthree months.
 9. The solid pharmaceutical composition according to claim2, wherein the solid pharmaceutical composition contains no more thanabout 0.0411% by weight of2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide after being stored in asealed container at about 25° C. and about 60% relative humidity forabout six months.
 10. The solid pharmaceutical composition according toclaim 2, wherein the solid pharmaceutical composition contains no morethan about 0.0562% by weight of2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide after being stored in asealed container at about 30° C. and about 65% relative humidity forabout six months.
 11. The solid pharmaceutical composition according toclaim 2, wherein the solid pharmaceutical composition contains no morethan about 0.4447% by weight of2-cyano-N-(4-trifluoromethyl-phenyl)-acetamide after being stored in anopen container at about 40° C. and about 75% relative humidity for aboutsix months.
 12. The solid pharmaceutical composition according to claim2, wherein the solid pharmaceutical composition contains no more thanabout 0.213% by weight of 2-cyano-N-(4-trifluoromethyl-phenyl)-acetamideafter being stored in a sealed container at about 40° C. and about 75%relative humidity for about six months.